Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Findings from the literature, and preliminary data reported in this application, suggest lipid measures, including brain-derived cholesterol species and lipid peroxidation products, may produce unique, readily detectable signatures in the blood of AD patients. These signatures may be indicators of AD-associated neurodegeneration, producing candidate biomarkers of disease progression. Thus far no longitudinal studies have been conducted in this area. This is important because the rate of change or accumulation of a biomarker may be a better indicator of disease progression than a single value or range at one time point. Such a biomarker could be used as a surrogate or secondary outcome measure in clinical trials of emerging therapies for AD, or may be a prognostic indicator of disease progression. A blood-based biomarker would be superior to CSF-based or brain imaging biomarkers with regard to cost, invasiveness and feasibility. We propose a proof-of-concept study to explore the clinical utility of 24S-hydroxycholesterol (24S-OHC), 24S-OHC/27- hydroxycholesterol ratio, 24S-OHC/cholesterol ratio and F2a-isoprostanes as blood-based biomarkers of AD-associated neurodegeneration using a longitudinal study design. We will recruit well-characterized patients with mild probable AD (pAD), amnestic mild cognitive impairment (MCI), and age-matched cognitively normal controls, 30 per group, from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). These individuals are already followed annually as part of the Center's Clinical Core. For the proposed study, individuals will be asked to provide fasting blood samples at three time points, during two regularly scheduled annual visits, and during a six month visit in between, at which point they will undergo additional cognitive testing. Additional years of follow-up beyond the duration of this study will be available through the JHADRC. Analyses will (1) Estimate the variability of plasma levels of each biomarker both within and between individuals at baseline, 6 months and 1 year and determine factors that effect this variability; (2) Compare the cross-sectional and longitudinal variations and trajectories in biomarkers for the three groups of individuals with varying AD pathology; (3) Determine whether baseline biomarker levels predict one-year cognitive decline; (4) Assess change in biomarker levels as subsequent predictors of cognition decline; and (5) Determine whether the sum of the biomarker levels over one year are related to intra-individual cognitive change. This R21 application proposes a proof-of-concept study to explore the clinical utility of blood- based lipid biomarkers, including 24S-hydroxycholesterol and F2a-isoprostanes, as indicators of Alzheimer's disease (AD)-associated neurodegeneration. Such a biomarker of neurodegeneration would have several applications, including prognosis after the onset of dementia, prognosis of conversion from mild cognitive impairment to dementia, or prognosis in the preclinical phases of the disease. A major application would be as a surrogate or secondary outcome measure in clinical trials of emerging therapies for AD. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]